PL201645B1 - Podstawione kwasy indoloalkanokarboksylowe, kompozycja farmaceutyczna i zastosowanie podstawionych kwasów indoloalkanokarboksylowych - Google Patents
Podstawione kwasy indoloalkanokarboksylowe, kompozycja farmaceutyczna i zastosowanie podstawionych kwasów indoloalkanokarboksylowychInfo
- Publication number
- PL201645B1 PL201645B1 PL348244A PL34824499A PL201645B1 PL 201645 B1 PL201645 B1 PL 201645B1 PL 348244 A PL348244 A PL 348244A PL 34824499 A PL34824499 A PL 34824499A PL 201645 B1 PL201645 B1 PL 201645B1
- Authority
- PL
- Poland
- Prior art keywords
- compound
- methyl
- indole
- acetic acid
- trifluorobenzothiazol
- Prior art date
Links
- 239000002253 acid Substances 0.000 title abstract description 10
- 150000007513 acids Chemical class 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 140
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 11
- 230000001684 chronic effect Effects 0.000 claims abstract description 5
- -1 methylene, methylene Chemical group 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 24
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical group C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 19
- 125000001153 fluoro group Chemical group F* 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 150000002431 hydrogen Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 5
- KOBFGCSHZBLYOW-UHFFFAOYSA-N 2-[2-methyl-5-phenyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C=1C=C2N(CC(O)=O)C(C)=C(C=3SC4=C(F)C=C(F)C(F)=C4N=3)C2=CC=1C1=CC=CC=C1 KOBFGCSHZBLYOW-UHFFFAOYSA-N 0.000 claims description 5
- VFRYWFLFAVFXIO-UHFFFAOYSA-N 2-[2-methyl-6-morpholin-4-yl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C1=C2N(CC(O)=O)C(C)=C(C=3SC4=C(F)C=C(F)C(F)=C4N=3)C2=CC=C1N1CCOCC1 VFRYWFLFAVFXIO-UHFFFAOYSA-N 0.000 claims description 5
- LJTZOVSFODOIIV-UHFFFAOYSA-N 2-[5-chloro-2-methyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C12=CC(Cl)=CC=C2N(CC(O)=O)C(C)=C1C1=NC2=C(F)C(F)=CC(F)=C2S1 LJTZOVSFODOIIV-UHFFFAOYSA-N 0.000 claims description 5
- 206010007749 Cataract diabetic Diseases 0.000 claims description 5
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 5
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 201000007025 diabetic cataract Diseases 0.000 claims description 5
- VVZCEUWTIRZKJJ-UHFFFAOYSA-N ethyl 2-[2-methyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetate Chemical compound C(C)OC(CN1C(=C(C2=CC=CC=C12)C=1SC2=C(N=1)C(=C(C=C2F)F)F)C)=O VVZCEUWTIRZKJJ-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical group 0.000 claims description 5
- 230000007823 neuropathy Effects 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- KYHVTMFADJNSGS-UHFFFAOYSA-N {3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1h-indol-1-yl}acetic acid Chemical compound C12=CC=CC=C2N(CC(=O)O)C=C1CC1=NC2=C(F)C(F)=CC(F)=C2S1 KYHVTMFADJNSGS-UHFFFAOYSA-N 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- XVWZZDJHMNCSHG-UHFFFAOYSA-N 2-[2,5-dimethyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C12=CC(C)=CC=C2N(CC(O)=O)C(C)=C1C1=NC2=C(F)C(F)=CC(F)=C2S1 XVWZZDJHMNCSHG-UHFFFAOYSA-N 0.000 claims description 4
- HCBULRDWWUHSOC-UHFFFAOYSA-N 2-[2,5-dimethyl-3-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]indol-1-yl]acetic acid Chemical compound C12=CC(C)=CC=C2N(CC(O)=O)C(C)=C1C1=NC2=CC(C(F)(F)F)=CC=C2S1 HCBULRDWWUHSOC-UHFFFAOYSA-N 0.000 claims description 4
- CKTQUOAACPEOFU-UHFFFAOYSA-N 2-[2,6-dimethyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C12=CC=C(C)C=C2N(CC(O)=O)C(C)=C1C1=NC2=C(F)C(F)=CC(F)=C2S1 CKTQUOAACPEOFU-UHFFFAOYSA-N 0.000 claims description 4
- HCEONJPEGLZCMZ-UHFFFAOYSA-N 2-[2,7-dimethyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C12=CC=CC(C)=C2N(CC(O)=O)C(C)=C1C1=NC2=C(F)C(F)=CC(F)=C2S1 HCEONJPEGLZCMZ-UHFFFAOYSA-N 0.000 claims description 4
- VBNFGLWTIQTREP-UHFFFAOYSA-N 2-[2-methyl-3-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]indol-1-yl]acetic acid Chemical compound C12=CC=CC=C2N(CC(O)=O)C(C)=C1C1=NC2=CC(C(F)(F)F)=CC=C2S1 VBNFGLWTIQTREP-UHFFFAOYSA-N 0.000 claims description 4
- JCBBUAGGFRHAAR-UHFFFAOYSA-N 2-[2-methyl-5-morpholin-4-yl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C=1C=C2N(CC(O)=O)C(C)=C(C=3SC4=C(F)C=C(F)C(F)=C4N=3)C2=CC=1N1CCOCC1 JCBBUAGGFRHAAR-UHFFFAOYSA-N 0.000 claims description 4
- BUQYFLKPQDSKSS-UHFFFAOYSA-N 2-[2-methyl-5-phenoxy-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C=1C=C2N(CC(O)=O)C(C)=C(C=3SC4=C(F)C=C(F)C(F)=C4N=3)C2=CC=1OC1=CC=CC=C1 BUQYFLKPQDSKSS-UHFFFAOYSA-N 0.000 claims description 4
- UNGJWLWQAXJOEO-UHFFFAOYSA-N 2-[2-methyl-5-phenylmethoxy-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C=1C=C2N(CC(O)=O)C(C)=C(C=3SC4=C(F)C=C(F)C(F)=C4N=3)C2=CC=1OCC1=CC=CC=C1 UNGJWLWQAXJOEO-UHFFFAOYSA-N 0.000 claims description 4
- IYIIESNRJJTDLA-UHFFFAOYSA-N 2-[3-[(3-nitrophenyl)methyl]indol-1-yl]acetic acid Chemical compound C12=CC=CC=C2N(CC(=O)O)C=C1CC1=CC=CC([N+]([O-])=O)=C1 IYIIESNRJJTDLA-UHFFFAOYSA-N 0.000 claims description 4
- CUNNSKIRHRLJMS-UHFFFAOYSA-N 2-[4-methyl-2-phenyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound N=1C2=C(F)C(F)=CC(F)=C2SC=1C=1C=2C(C)=CC=CC=2N(CC(O)=O)C=1C1=CC=CC=C1 CUNNSKIRHRLJMS-UHFFFAOYSA-N 0.000 claims description 4
- DFSHWYWKHTUEAJ-UHFFFAOYSA-N 2-[5-fluoro-2-methyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C12=CC(F)=CC=C2N(CC(O)=O)C(C)=C1C1=NC2=C(F)C(F)=CC(F)=C2S1 DFSHWYWKHTUEAJ-UHFFFAOYSA-N 0.000 claims description 4
- OVRDKEPIWAYWQW-UHFFFAOYSA-N 2-[6-chloro-2-methyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C12=CC=C(Cl)C=C2N(CC(O)=O)C(C)=C1C1=NC2=C(F)C(F)=CC(F)=C2S1 OVRDKEPIWAYWQW-UHFFFAOYSA-N 0.000 claims description 4
- DBRVNNBRSNYWLT-UHFFFAOYSA-N 2-[6-fluoro-2-methyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C12=CC=C(F)C=C2N(CC(O)=O)C(C)=C1C1=NC2=C(F)C(F)=CC(F)=C2S1 DBRVNNBRSNYWLT-UHFFFAOYSA-N 0.000 claims description 4
- HMBWWSMTYLJAJP-UHFFFAOYSA-N 2-[7-fluoro-2-methyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C12=CC=CC(F)=C2N(CC(O)=O)C(C)=C1C1=NC2=C(F)C(F)=CC(F)=C2S1 HMBWWSMTYLJAJP-UHFFFAOYSA-N 0.000 claims description 4
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 4
- TZWDAJXRUPUEAI-UHFFFAOYSA-N ethyl 2-[2-methyl-3-(3-nitrophenyl)indol-1-yl]acetate Chemical compound C(C)OC(CN1C(=C(C2=CC=CC=C12)C1=CC(=CC=C1)[N+](=O)[O-])C)=O TZWDAJXRUPUEAI-UHFFFAOYSA-N 0.000 claims description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- GFSCGVIGCOFBJX-UHFFFAOYSA-N 2-[2-methyl-6-phenyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C1=C2N(CC(O)=O)C(C)=C(C=3SC4=C(F)C=C(F)C(F)=C4N=3)C2=CC=C1C1=CC=CC=C1 GFSCGVIGCOFBJX-UHFFFAOYSA-N 0.000 claims description 3
- GCNDTOHGLQBVIH-UHFFFAOYSA-N 2-[3-(6-chloro-1,3-benzothiazol-2-yl)-2-methylindol-1-yl]acetic acid Chemical compound C12=CC=CC=C2N(CC(O)=O)C(C)=C1C1=NC2=CC=C(Cl)C=C2S1 GCNDTOHGLQBVIH-UHFFFAOYSA-N 0.000 claims description 3
- SKKDXNWINHMESM-UHFFFAOYSA-N 2-[4-chloro-2-methyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C12=C(Cl)C=CC=C2N(CC(O)=O)C(C)=C1C1=NC2=C(F)C(F)=CC(F)=C2S1 SKKDXNWINHMESM-UHFFFAOYSA-N 0.000 claims description 3
- WOUZKZPEOGTKMC-UHFFFAOYSA-N 2-[5-bromo-2-methyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C12=CC(Br)=CC=C2N(CC(O)=O)C(C)=C1C1=NC2=C(F)C(F)=CC(F)=C2S1 WOUZKZPEOGTKMC-UHFFFAOYSA-N 0.000 claims description 3
- DILGZMIXUSQOLA-UHFFFAOYSA-N 2-[6-bromo-2-methyl-3-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]indol-1-yl]acetic acid Chemical compound C12=CC=C(Br)C=C2N(CC(O)=O)C(C)=C1C1=NC2=CC(C(F)(F)F)=CC=C2S1 DILGZMIXUSQOLA-UHFFFAOYSA-N 0.000 claims description 3
- HVUIEHYEYLFSFM-UHFFFAOYSA-N 2-[6-methoxy-2-methyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound COC1=CC=C2C(=C(N(C2=C1)CC(=O)O)C)C=1SC2=C(N=1)C(=C(C=C2F)F)F HVUIEHYEYLFSFM-UHFFFAOYSA-N 0.000 claims description 3
- LGHOGBGSCCLCQZ-UHFFFAOYSA-N 2-[7-bromo-2-methyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C12=CC=CC(Br)=C2N(CC(O)=O)C(C)=C1C1=NC2=C(F)C(F)=CC(F)=C2S1 LGHOGBGSCCLCQZ-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- UXEQTQLGTPBEQZ-UHFFFAOYSA-N 2-[3-[(5-fluoro-1,3-benzothiazol-2-yl)methyl]indol-1-yl]acetic acid Chemical compound C12=CC=CC=C2N(CC(=O)O)C=C1CC1=NC2=CC(F)=CC=C2S1 UXEQTQLGTPBEQZ-UHFFFAOYSA-N 0.000 claims description 2
- DYNHZTFLLXJYDQ-UHFFFAOYSA-N 2-[3-[(6-fluoro-1,3-benzothiazol-2-yl)methyl]indol-1-yl]acetic acid Chemical compound C12=CC=CC=C2N(CC(=O)O)C=C1CC1=NC2=CC=C(F)C=C2S1 DYNHZTFLLXJYDQ-UHFFFAOYSA-N 0.000 claims description 2
- NAFDKROMHJGVHR-UHFFFAOYSA-N 2-[5-methoxy-2-methyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound FC1=CC(F)=C2SC(C3=C(C)N(CC(O)=O)C4=CC=C(C=C43)OC)=NC2=C1F NAFDKROMHJGVHR-UHFFFAOYSA-N 0.000 claims description 2
- BKHJELPVVCKDEJ-UHFFFAOYSA-N 2-[7-chloro-2-methyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetic acid Chemical compound C12=CC=CC(Cl)=C2N(CC(O)=O)C(C)=C1C1=NC2=C(F)C(F)=CC(F)=C2S1 BKHJELPVVCKDEJ-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- BGZUMCLKHASORJ-UHFFFAOYSA-N ethyl 2-[5-chloro-2-methyl-3-(4,5,7-trifluoro-1,3-benzothiazol-2-yl)indol-1-yl]acetate Chemical compound C(C)OC(CN1C(=C(C2=CC(=CC=C12)Cl)C=1SC2=C(N=1)C(=C(C=C2F)F)F)C)=O BGZUMCLKHASORJ-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 39
- 238000003786 synthesis reaction Methods 0.000 abstract description 16
- 230000015572 biosynthetic process Effects 0.000 abstract description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 101
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 90
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 70
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- 238000002360 preparation method Methods 0.000 description 46
- 238000005481 NMR spectroscopy Methods 0.000 description 45
- 239000000203 mixture Substances 0.000 description 42
- 235000019439 ethyl acetate Nutrition 0.000 description 41
- 239000000243 solution Substances 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 34
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 239000000543 intermediate Substances 0.000 description 26
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 22
- MYTGFBZJLDLWQG-UHFFFAOYSA-N 5-chloro-1h-indole Chemical compound ClC1=CC=C2NC=CC2=C1 MYTGFBZJLDLWQG-UHFFFAOYSA-N 0.000 description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 17
- 150000002475 indoles Chemical class 0.000 description 17
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
- 235000019341 magnesium sulphate Nutrition 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 14
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000003288 aldose reductase inhibitor Substances 0.000 description 12
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 108010053754 Aldehyde reductase Proteins 0.000 description 10
- 102100027265 Aldo-keto reductase family 1 member B1 Human genes 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- 229910001868 water Inorganic materials 0.000 description 10
- 101000836540 Homo sapiens Aldo-keto reductase family 1 member B1 Proteins 0.000 description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- 238000003818 flash chromatography Methods 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 7
- 238000007429 general method Methods 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000000377 silicon dioxide Substances 0.000 description 7
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- 238000007832 transition metal-catalyzed coupling reaction Methods 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Ophthalmology & Optometry (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8014398P | 1998-03-31 | 1998-03-31 | |
| PCT/US1999/007116 WO1999050268A2 (en) | 1998-03-31 | 1999-03-31 | Substituted indolealkanoic acids |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| PL348244A1 PL348244A1 (en) | 2002-05-20 |
| PL201645B1 true PL201645B1 (pl) | 2009-04-30 |
Family
ID=22155536
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PL348244A PL201645B1 (pl) | 1998-03-31 | 2002-03-01 | Podstawione kwasy indoloalkanokarboksylowe, kompozycja farmaceutyczna i zastosowanie podstawionych kwasów indoloalkanokarboksylowych |
Country Status (29)
| Country | Link |
|---|---|
| US (9) | US6214991B1 (hu) |
| EP (1) | EP1066283B1 (hu) |
| JP (2) | JP3494990B2 (hu) |
| KR (1) | KR100584650B1 (hu) |
| CN (1) | CN1205207C (hu) |
| AP (1) | AP2000001929A0 (hu) |
| AT (1) | ATE269861T1 (hu) |
| AU (1) | AU774929B2 (hu) |
| BG (1) | BG65446B1 (hu) |
| BR (1) | BR9909358A (hu) |
| CA (1) | CA2383983C (hu) |
| CZ (1) | CZ300706B6 (hu) |
| DE (1) | DE69918278T2 (hu) |
| EE (1) | EE200000573A (hu) |
| ES (1) | ES2224632T3 (hu) |
| HU (1) | HUP0101672A3 (hu) |
| ID (1) | ID27884A (hu) |
| IL (2) | IL138711A0 (hu) |
| MX (1) | MXPA02003122A (hu) |
| NO (1) | NO20004900L (hu) |
| NZ (1) | NZ507172A (hu) |
| OA (1) | OA11622A (hu) |
| PL (1) | PL201645B1 (hu) |
| SK (1) | SK7522001A3 (hu) |
| TR (1) | TR200002869T2 (hu) |
| TW (1) | TWI243163B (hu) |
| WO (1) | WO1999050268A2 (hu) |
| YU (1) | YU59600A (hu) |
| ZA (1) | ZA200005577B (hu) |
Families Citing this family (51)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| OA11622A (en) * | 1998-03-31 | 2004-09-16 | Inst For Pharm Discovery Inc | Substituted indolealkanoic acids. |
| TNSN99224A1 (fr) * | 1998-12-01 | 2005-11-10 | Inst For Pharm Discovery Inc | Methodes de reduction des niveaux de glucose et triglyceride en serum et pour suppression de l'antigenese utilisant les acides la indolealkanoique |
| CA2378047A1 (en) * | 1999-07-15 | 2001-01-25 | Methvin Isaac | Heterocyclic compounds for the treatment of migraine |
| WO2001064205A2 (en) * | 2000-03-02 | 2001-09-07 | The Institutes For Pharmaceutical Discovery, Llc | Compositions containing a substituted indolealkanoic acid and an angiotensin converting enzyme inhibitor |
| AU2001259668A1 (en) * | 2000-05-09 | 2001-11-20 | The Institute For Pharmaceutical Discovery Llc | Methods for testing compounds useful for treating diabetic complications |
| WO2002051805A1 (de) | 2000-12-27 | 2002-07-04 | Bayer Aktiengesellschaft | Indol-derivate |
| TWI224101B (en) | 2001-06-20 | 2004-11-21 | Wyeth Corp | Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1) |
| JP4399253B2 (ja) | 2001-06-20 | 2010-01-13 | ワイス | プラスミノゲンアクチベーターインヒビター−１（ｐａｉ−１）のインヒビターとしての、置換されたインドール酸誘導体 |
| EP1465629B1 (en) | 2002-01-18 | 2007-03-14 | Aryx Therapeutics | 5-ht3 receptor antagonists and methods of use |
| CA2395871A1 (en) * | 2002-07-26 | 2004-01-26 | The Institutes For Pharmaceutical Discovery, Llc | Substituted indolealkanoic acids derivatives and formulations containing same for use in treatment of diabetic complications |
| MXPA05001011A (es) * | 2002-07-26 | 2005-06-08 | Inst For Pharm Discovery Inc | Derivado de acidos indolalcanoicos substituidos y formulaciones que lo contienen para uso en tratamiento de complicaciones diabeticas. |
| CN100457730C (zh) * | 2002-08-29 | 2009-02-04 | 默克公司 | 具有抗糖尿病活性的吲哚化合物 |
| ATE430731T1 (de) | 2002-12-10 | 2009-05-15 | Wyeth Corp | Substituierte indoloxoacetylaminoessigsäurederivate als inhibitoren des plasminogenaktivatorinhibitors-1 (pai-1) |
| BR0316583A (pt) | 2002-12-10 | 2005-10-04 | Wyeth Corp | Derivados de ácido acético 3-alquil e 3-arilalquil 1h-indol-1-il substituìdo como inibidores do inibidor-1 do ativador do plasminogênio (pai-1) |
| ATE331709T1 (de) | 2002-12-10 | 2006-07-15 | Wyeth Corp | Substituierte 3-carbonyl-1-yl essigsäure derivate als plasminogen aktivator inhibitor(pai-1) inhibitoren |
| UA80453C2 (en) | 2002-12-10 | 2007-09-25 | Derivatives of substituted dyhydropyranoindol-3,4-dion as inhibitors of plasminogen activator inhibitor-1 (pai-1) | |
| US7259182B2 (en) | 2002-12-10 | 2007-08-21 | Wyeth | Aryl, aryloxy, and aklyloxy substituted 1H-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) |
| EP1620088A4 (en) * | 2003-04-28 | 2007-08-29 | Bayer Pharmaceuticals Corp | ACETIC INDOLE ACID DERIVATIVES AND THEIR USE AS PHARMACEUTICAL AGENTS |
| KR20060006953A (ko) * | 2003-04-30 | 2006-01-20 | 디 인스티튜트스 포 파마슈티컬 디스커버리, 엘엘씨 | 치환된 카르복실산 |
| AU2004261667A1 (en) * | 2003-08-01 | 2005-02-10 | Genelabs Technologies, Inc. | Bicyclic imidazol derivatives against Flaviviridae |
| US7446201B2 (en) | 2003-09-25 | 2008-11-04 | Wyeth | Substituted heteroaryl benzofuran acids |
| US7442805B2 (en) | 2003-09-25 | 2008-10-28 | Wyeth | Substituted sulfonamide-indoles |
| US7163954B2 (en) | 2003-09-25 | 2007-01-16 | Wyeth | Substituted naphthyl benzothiophene acids |
| US7411083B2 (en) | 2003-09-25 | 2008-08-12 | Wyeth | Substituted acetic acid derivatives |
| US7141592B2 (en) | 2003-09-25 | 2006-11-28 | Wyeth | Substituted oxadiazolidinediones |
| US7582773B2 (en) | 2003-09-25 | 2009-09-01 | Wyeth | Substituted phenyl indoles |
| US7351726B2 (en) | 2003-09-25 | 2008-04-01 | Wyeth | Substituted oxadiazolidinediones |
| US7265148B2 (en) | 2003-09-25 | 2007-09-04 | Wyeth | Substituted pyrrole-indoles |
| US7268159B2 (en) | 2003-09-25 | 2007-09-11 | Wyeth | Substituted indoles |
| US7332521B2 (en) | 2003-09-25 | 2008-02-19 | Wyeth | Substituted indoles |
| GB0324763D0 (en) | 2003-10-23 | 2003-11-26 | Oxagen Ltd | Use of compounds in therapy |
| JP2008518926A (ja) * | 2004-10-28 | 2008-06-05 | ジ インスティチューツ フォー ファーマシューティカル ディスカバリー、エルエルシー | 置換フェニルアルカン酸 |
| CN101103026A (zh) * | 2005-01-14 | 2008-01-09 | 健亚生物科技公司 | 用于治疗病毒感染的吲哚衍生物 |
| GB0505048D0 (en) * | 2005-03-11 | 2005-04-20 | Oxagen Ltd | Compounds with PGD antagonist activity |
| US20080051384A1 (en) * | 2006-07-14 | 2008-02-28 | Genelabs Technologies, Inc. | Antiviral agents |
| RU2458918C2 (ru) | 2006-07-22 | 2012-08-20 | Оксаген Лимитед | Соединения, обладающие антагонистической активностью по отношению к crth2 |
| US7750027B2 (en) * | 2008-01-18 | 2010-07-06 | Oxagen Limited | Compounds having CRTH2 antagonist activity |
| RU2503672C2 (ru) | 2008-01-18 | 2014-01-10 | Оксаген Лимитед | Соединения, обладающие активностью антагонистов crth2 |
| EP2265581A1 (en) | 2008-01-22 | 2010-12-29 | Oxagen Limited | Compounds having crth2 antagonist activity |
| WO2009093029A1 (en) | 2008-01-22 | 2009-07-30 | Oxagen Limited | Compounds having crth2 antagonist activity |
| GB2457040A (en) * | 2008-01-30 | 2009-08-05 | Oxagen Ltd | 1-Acetic acid indole derivatives with PGD2 activity |
| NZ624963A (en) | 2009-04-29 | 2016-07-29 | Amarin Pharmaceuticals Ie Ltd | Pharmaceutical compositions comprising epa and a cardiovascular agent and methods of using the same |
| EP4124620A1 (en) * | 2010-07-16 | 2023-02-01 | The Trustees of Columbia University in the City of New York | Aldose reductase inhibitors and uses thereof |
| US8916563B2 (en) | 2010-07-16 | 2014-12-23 | The Trustees Of Columbia University In The City Of New York | Aldose reductase inhibitors and uses thereof |
| GB201322273D0 (en) | 2013-12-17 | 2014-01-29 | Atopix Therapeutics Ltd | Process |
| GB201407820D0 (en) | 2014-05-02 | 2014-06-18 | Atopix Therapeutics Ltd | Polymorphic form |
| GB201407807D0 (en) | 2014-05-02 | 2014-06-18 | Atopix Therapeutics Ltd | Polymorphic form |
| PT3352754T (pt) | 2016-06-21 | 2020-12-07 | Univ Columbia | Inibidores da aldose redutase e métodos de seu uso |
| EP3658142B1 (en) | 2017-07-28 | 2024-04-17 | Applied Therapeutics, Inc. | Compositions and methods for treating galactosemia |
| US11530186B2 (en) | 2018-03-29 | 2022-12-20 | H. Lee Moffitt Cancer Center and Research Center Institute, Inc. | Inhibitors for the β-catenin / T-cell factor protein-protein interaction |
| EP3966320A4 (en) | 2019-05-07 | 2023-10-25 | University of Miami | TREATMENT AND DETECTION OF HEREDITARY NEUROPATHIES AND ASSOCIATED DISORDERS |
Family Cites Families (38)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3557142A (en) * | 1968-02-20 | 1971-01-19 | Sterling Drug Inc | 4,5,6,7-tetrahydro-indole-lower-alkanoic acids and esters |
| IE47592B1 (en) | 1977-12-29 | 1984-05-02 | Ici Ltd | Enzyme inhibitory phthalazin-4-ylacetic acid derivatives, pharmaceutical compositions thereof,and process for their manufacture |
| DK151884C (da) * | 1979-03-07 | 1988-06-13 | Pfizer | Analogifremgangsmaade til fremstilling af 3-(1-imidazolylalkyl)indolderivater eller farmaceutisk acceptable syreadditionssalte deraf |
| JPS55167282A (en) | 1979-06-12 | 1980-12-26 | Fujisawa Pharmaceut Co Ltd | Piperazine derivative or its salt and its preparation |
| US4283539A (en) | 1979-12-18 | 1981-08-11 | Pfizer Inc. | Isoquinoline acetic acids |
| US4363912A (en) * | 1980-12-15 | 1982-12-14 | Pfizer Inc. | Indole thromboxane synthetase inhibitors |
| US4442118A (en) | 1981-07-23 | 1984-04-10 | Ayerst, Mckenna & Harrison, Inc. | Aldose reductase inhibition by 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid |
| GB8607294D0 (en) | 1985-04-17 | 1986-04-30 | Ici America Inc | Heterocyclic amide derivatives |
| IL80475A (en) * | 1985-11-07 | 1993-01-31 | Pfizer | Heterocyclic-substituted 4-oxo (or thio)-3h- phthalazinyl-acetic acid derivatives and pharmaceutical compositions containing them |
| US4939140A (en) | 1985-11-07 | 1990-07-03 | Pfizer Inc. | Heterocyclic oxophthalazinyl acetic acids |
| US4960785A (en) * | 1988-12-16 | 1990-10-02 | Pfizer Inc. | Indolinone derivatives |
| WO1993012786A1 (en) * | 1986-07-10 | 1993-07-08 | Howard Harry R Jr | Indolinone derivatives |
| US4868301A (en) * | 1987-06-09 | 1989-09-19 | Pfizer Inc. | Processes and intermediates for the preparation of oxophthalazinyl acetic acids having benzothiazole or other heterocyclic side chains |
| US5064852A (en) * | 1988-12-16 | 1991-11-12 | Pfizer Inc. | Indolinone derivatives |
| KR920700210A (ko) | 1989-03-31 | 1992-02-19 | 기따미 가즈히꼬 | 신규 이미다졸 유도체, 그의 제법 및 그의 의약용도 |
| US4996204A (en) * | 1989-05-11 | 1991-02-26 | Pfizer Inc. | Pyrido[2,3-d]pyridazinones as aldose reductase inhibitors |
| FR2647676A1 (fr) * | 1989-06-05 | 1990-12-07 | Union Pharma Scient Appl | Nouveaux derives de pyridazinone, leurs procedes de preparation, medicaments les contenant, utiles notamment comme inhibiteurs de l'aldose reductase |
| GB8916774D0 (en) * | 1989-07-21 | 1989-09-06 | Bayer Ag | New indole derivatives,a process for their preparation and their use in medicaments |
| US5304557A (en) | 1989-12-15 | 1994-04-19 | Pfizer Inc. | Substituted oxoophthalazinyl acetic acids and analogs thereof |
| GB9011335D0 (en) | 1990-05-21 | 1990-07-11 | Fujisawa Pharmaceutical Co | Indolebutyric acid derivatives and process for preparation thereof |
| US5312829A (en) * | 1990-05-21 | 1994-05-17 | Fujisawa Pharmaceutical Co., Ltd. | Indole derivatives |
| US5236945A (en) * | 1990-06-11 | 1993-08-17 | Pfizer Inc. | 1H-indazole-3-acetic acids as aldose reductase inhibitors |
| US5116753A (en) | 1991-07-30 | 1992-05-26 | The Salk Institute For Biological Studies | Maintenance of pancreatic islets |
| JPH0641071A (ja) * | 1991-09-06 | 1994-02-15 | Taisho Pharmaceut Co Ltd | インドール酢酸エステル誘導体 |
| GB9122590D0 (en) | 1991-10-24 | 1991-12-04 | Lilly Industries Ltd | Pharmaceutical compounds |
| US5391551A (en) | 1993-05-10 | 1995-02-21 | Pfizer Inc. | Method of lowering blood lipid levels |
| GB9317764D0 (en) * | 1993-08-26 | 1993-10-13 | Pfizer Ltd | Therapeutic compound |
| GB9409583D0 (en) | 1994-05-13 | 1994-07-06 | Pfizer Ltd | Indoles |
| US5641800A (en) * | 1994-07-21 | 1997-06-24 | Eli Lilly And Company | 1H-indole-1-functional sPLA2 inhibitors |
| TW401301B (en) | 1994-10-07 | 2000-08-11 | Takeda Chemical Industries Ltd | Antihypertriglyceridemic composition |
| US5700819A (en) * | 1994-11-29 | 1997-12-23 | Grelan Pharmaceutical Co., Ltd. | 2-substituted benzothiazole derivatives and prophylactic and therapeutic agents for the treatment of diabetic complications |
| IL117208A0 (en) * | 1995-02-23 | 1996-06-18 | Nissan Chemical Ind Ltd | Indole type thiazolidines |
| TR199700993T1 (xx) * | 1995-03-20 | 1998-03-21 | Eli Lilly And Company | 5-ikameli-3-(1,2,3,6-tetrahidropridin-4-il)- ve 3-(piperidin-4-il)-1H-indoller: yeni 5-HT1F agonistler. |
| JPH09165371A (ja) | 1995-10-09 | 1997-06-24 | Sankyo Co Ltd | 複素環化合物を含有する医薬 |
| DE19636150A1 (de) * | 1996-09-06 | 1998-03-12 | Asta Medica Ag | N-substituierte Indol-3-glyoxylamide mit antiasthmatischer, antiallergischer und immunsuppressiver/immunmodulierender Wirkung |
| OA11622A (en) * | 1998-03-31 | 2004-09-16 | Inst For Pharm Discovery Inc | Substituted indolealkanoic acids. |
| TNSN99224A1 (fr) * | 1998-12-01 | 2005-11-10 | Inst For Pharm Discovery Inc | Methodes de reduction des niveaux de glucose et triglyceride en serum et pour suppression de l'antigenese utilisant les acides la indolealkanoique |
| WO2001064205A2 (en) * | 2000-03-02 | 2001-09-07 | The Institutes For Pharmaceutical Discovery, Llc | Compositions containing a substituted indolealkanoic acid and an angiotensin converting enzyme inhibitor |
-
1999
- 1999-03-31 OA OA1200000269A patent/OA11622A/en unknown
- 1999-03-31 CZ CZ20003607A patent/CZ300706B6/cs not_active IP Right Cessation
- 1999-03-31 EE EEP200000573A patent/EE200000573A/xx unknown
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2000
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2001
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2002
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2004
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2006
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2007
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2010
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